Advertisement

Investigational New Drugs

, Volume 31, Issue 5, pp 1375–1383 | Cite as

The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer

  • Mohamed A. Khalil
  • Wei Qiao
  • Peter Carlson
  • Binsah George
  • Milind Javle
  • Michael Overman
  • Gauri Varadhachary
  • Robert A. Wolff
  • James L. Abbruzzese
  • David R. FogelmanEmail author
SHORT REPORT

Abstract

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0–1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value = 0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS = 2–3) had worse survival as compared to patients with better performance status (PS = 0–1, p = 0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p = 0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p = 0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.

Keywords

Pancreatic cancer Chemotherapy Platinum Gemcitabine Erlotinib Smoking Nicotine 

Notes

Conflict of Interest

None of the authors of this paper have any relevant conflicts of interest to disclose. This study was funded by a charitable donation from the Crain-Maling Foundation, Chicago, IL.

References

  1. 1.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30. doi: https://doi.org/10.3322/caac.21166 CrossRefGoogle Scholar
  2. 2.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol Off J Am Soc Clin Oncol 15(6):2403–2413CrossRefGoogle Scholar
  3. 3.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, National Cancer Institute of Canada Clinical Trials G (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol Off J Am Soc Clin Oncol 25(15):1960–1966. doi: https://doi.org/10.1200/JCO.2006.07.9525 CrossRefGoogle Scholar
  4. 4.
    Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol Off J Am Soc Clin Oncol 24(24):3946–3952. doi: https://doi.org/10.1200/JCO.2005.05.1490 CrossRefGoogle Scholar
  5. 5.
    Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A, Giscad, Gercor (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol Off J Am Soc Clin Oncol 23(15):3509–3516. doi: https://doi.org/10.1200/JCO.2005.06.023 CrossRefGoogle Scholar
  6. 6.
    Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82. doi: https://doi.org/10.1186/1471-2407-8-82 CrossRefGoogle Scholar
  7. 7.
    Heinemann V, Labianca R, Hinke A, Louvet C (2007) Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. Ann Oncol Off J Eur Soc Med Oncol/ESMO 18(10):1652–1659. doi: https://doi.org/10.1093/annonc/mdm283 CrossRefGoogle Scholar
  8. 8.
    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of U, Intergroup P (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. doi: https://doi.org/10.1056/NEJMoa1011923 CrossRefGoogle Scholar
  9. 9.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53(282):457–481CrossRefGoogle Scholar
  10. 10.
    Cox DR (1972) Regression models and life-tables. J R Stat Soc Ser B (Methodological) 34(2):187–220Google Scholar
  11. 11.
    Hwang IG, Jang JS, Oh SY, Lee S, Kwon HC, Lee GW, Go S, Kang MH, Cha YJ, Kang JH (2012) A phase II trial of Erlotinib in combination with gemcitabine and cisplatin in advanced pancreatic cancer. Investig New Drugs 30(6):2371–2376. doi: https://doi.org/10.1007/s10637-012-9792-z CrossRefGoogle Scholar
  12. 12.
    Tas F, Sen F, Odabas H, Kilic L, Keskin S, Yildiz I (2012) Performance status of patients is the major prognostic factor at all stages of pancreatic cancer. Int J Clin Oncol/Jpn Soc Clin Oncol. doi: https://doi.org/10.1007/s10147-012-0474-9
  13. 13.
    Sawaki A, Kanemitsu Y, Mizuno N, Takahashi K, Nakamura T, Ioka T, Tanaka S, Nakaizumi A, Salem AA, Ueda R, Yamao K (2008) Practical prognostic index for patients with metastatic pancreatic cancer treated with gemcitabine. J Gastroenterol Hepatol 23(8 Pt 1):1292–1297. doi: https://doi.org/10.1111/j.1440-1746.2006.04734.x CrossRefGoogle Scholar
  14. 14.
    Mok T, Wu YL, Au JS, Zhou C, Zhang L, Perng RP, Park K (2010) Efficacy and safety of erlotinib in 1242 East/South-East Asian patients with advanced non-small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 5(10):1609–1615. doi: https://doi.org/10.1097/JTO.0b013e3181e15d55 Google Scholar
  15. 15.
    Kosaka T, Yatabe Y, Onozato R, Kuwano H, Mitsudomi T (2009) Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thorac Oncol 4(1):22–29CrossRefGoogle Scholar
  16. 16.
    Humphris JL, Chang DK, Johns AL, Scarlett CJ, Pajic M, Jones MD, Colvin EK, Nagrial A, Chin VT, Chantrill LA, Samra JS, Gill AJ, Kench JG, Merrett ND, Das A, Musgrove EA, Sutherland RL, Biankin AV, Network NSWPC (2012) The prognostic and predictive value of serum CA19.9 in pancreatic cancer. Ann Oncol Off J Eur Soc Med Oncol/ESMO 23(7):1713–1722. doi: https://doi.org/10.1093/annonc/mdr561 CrossRefGoogle Scholar
  17. 17.
    Hartwig W, Strobel O, Hinz U, Fritz S, Hackert T, Roth C, Buchler MW, Werner J (2012) CA19-9 in potentially resectable pancreatic cancer: perspective to adjust surgical and perioperative therapy. Ann Surg Oncol. doi: https://doi.org/10.1245/s10434-012-2809-1
  18. 18.
    Hammad N, Heilbrun LK, Philip PA, Shields AF, Zalupski MM, Venkatramanamoorthy R, El-Rayes BF (2010) CA19-9 as a predictor of tumor response and survival in patients with advanced pancreatic cancer treated with gemcitabine based chemotherapy. Asia Pac J Clin Oncol 6(2):98–105. doi: https://doi.org/10.1111/j.1743-7563.2010.01290.x CrossRefGoogle Scholar
  19. 19.
    Haas M, Heinemann V, Kullmann F, Laubender RP, Klose C, Bruns CJ, Holdenrieder S, Modest DP, Schulz C, Boeck S (2013) Prognostic value of CA 19–9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol. doi: https://doi.org/10.1007/s00432-012-1371-3
  20. 20.
    Vainshtein JM, Schipper M, Zalupski MM, Lawrence TS, Abrams R, Francis IR, Khan G, Leslie W, Ben-Josef E (2012) Prognostic significance of carbohydrate antigen 19–9 in unresectable locally advanced pancreatic cancer treated with dose-escalated intensity modulated radiation therapy and concurrent full-dose gemcitabine: analysis of a prospective phase 1/2 dose escalation study. Int J Radiat Oncol Biol Phys. doi: https://doi.org/10.1016/j.ijrobp.2012.11.020
  21. 21.
    Dakik HK, Moskovic DJ, Carlson PJ, Tamm EP, Qiao W, Wolff RA, Abbruzzese JL, Fogelman DR (2012) The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol 69(2):425–430. doi: https://doi.org/10.1007/s00280-011-1705-x CrossRefGoogle Scholar
  22. 22.
    Ghosn M, Saroufim A, Kattan J, Chahine G, Nasr F, Farhat F (2012) Sequential FOLFOX-6 and gemcitabine for locally advanced and/or metastatic pancreatic cancer. Med Oncol 29(4):2831–2837. doi: https://doi.org/10.1007/s12032-012-0197-9 CrossRefGoogle Scholar
  23. 23.
    Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA (2008) Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer 113(8):2046–2052. doi: https://doi.org/10.1002/cncr.23810 CrossRefGoogle Scholar
  24. 24.
    Reni M, Cereda S, Rognone A, Belli C, Ghidini M, Longoni S, Fugazza C, Rezzonico S, Passoni P, Slim N, Balzano G, Nicoletti R, Cappio S, Doglioni C, Villa E (2012) A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemother Pharmacol 69(1):115–123. doi: https://doi.org/10.1007/s00280-011-1680-2 CrossRefGoogle Scholar
  25. 25.
    De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr (2012) A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol 69(2):415–424. doi: https://doi.org/10.1007/s00280-011-1704-y CrossRefGoogle Scholar
  26. 26.
    Ko AH, Truong TG, Kantoff E, Jones KA, Dito E, Ong A, Tempero MA (2012) A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer. Cancer Chemother Pharmacol 70(6):875–881. doi: https://doi.org/10.1007/s00280-012-1979-7 CrossRefGoogle Scholar
  27. 27.
    Iodice S, Gandini S, Maisonneuve P, Lowenfels AB (2008) Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbeck’s Arch Surg/Deut Ges Chir 393(4):535–545. doi: https://doi.org/10.1007/s00423-007-0266-2 CrossRefGoogle Scholar
  28. 28.
    Lynch SM, Vrieling A, Lubin JH, Kraft P, Mendelsohn JB, Hartge P, Canzian F, Steplowski E, Arslan AA, Gross M, Helzlsouer K, Jacobs EJ, LaCroix A, Petersen G, Zheng W, Albanes D, Amundadottir L, Bingham SA, Boffetta P, Boutron-Ruault MC, Chanock SJ, Clipp S, Hoover RN, Jacobs K, Johnson KC, Kooperberg C, Luo J, Messina C, Palli D, Patel AV, Riboli E, Shu XO, Rodriguez Suarez L, Thomas G, Tjonneland A, Tobias GS, Tong E, Trichopoulos D, Virtamo J, Ye W, Yu K, Zeleniuch-Jacquette A, Bueno-de-Mesquita HB, Stolzenberg-Solomon RZ (2009) Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Am J Epidemiol 170(4):403–413. doi: https://doi.org/10.1093/aje/kwp134 CrossRefGoogle Scholar
  29. 29.
    Bosetti C, Lucenteforte E, Silverman DT, Petersen G, Bracci PM, Ji BT, Negri E, Li D, Risch HA, Olson SH, Gallinger S, Miller AB, Bueno-de-Mesquita HB, Talamini R, Polesel J, Ghadirian P, Baghurst PA, Zatonski W, Fontham E, Bamlet WR, Holly EA, Bertuccio P, Gao YT, Hassan M, Yu H, Kurtz RC, Cotterchio M, Su J, Maisonneuve P, Duell EJ, Boffetta P, La Vecchia C (2012) Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case–control Consortium (Panc4). Ann Oncol Off J Eur Soc Med Oncol/ESMO 23(7):1880–1888. doi: https://doi.org/10.1093/annonc/mdr541 CrossRefGoogle Scholar
  30. 30.
    Duell EJ (2012) Epidemiology and potential mechanisms of tobacco smoking and heavy alcohol consumption in pancreatic cancer. Mol Carcinog 51(1):40–52. doi: https://doi.org/10.1002/mc.20786 CrossRefGoogle Scholar
  31. 31.
    Blackford A, Parmigiani G, Kensler TW, Wolfgang C, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Klein A, Cameron JL, Olino K, Schulick R, Winter J, Vogelstein B, Velculescu VE, Kinzler KW, Hruban RH (2009) Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res 69(8):3681–3688. doi: https://doi.org/10.1158/0008-5472.CAN-09-0015 CrossRefGoogle Scholar
  32. 32.
    Trevino JG, Pillai S, Kunigal S, Singh S, Fulp WJ, Centeno BA, Chellappan SP (2012) Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma. Neoplasia 14(12):1102–1114CrossRefGoogle Scholar
  33. 33.
    Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ (2006) Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res Off J Am Assoc Cancer Res 12(7 Pt 1):2166–2171. doi: https://doi.org/10.1158/1078-0432.CCR-05-2235 CrossRefGoogle Scholar
  34. 34.
    Clark GM, Zborowski DM, Santabarbara P, Ding K, Whitehead M, Seymour L, Shepherd FA, National Cancer Institute of Canada Clinical Trials G (2006) Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 7(6):389–394CrossRefGoogle Scholar
  35. 35.
    Faehling M, Eckert R, Kuom S, Kamp T, Stoiber KM, Schumann C (2010) Benefit of erlotinib in patients with non-small-cell lung cancer is related to smoking status, gender, skin rash and radiological response but not to histology and treatment line. Oncology 78(3–4):249–258. doi: https://doi.org/10.1159/000315731 CrossRefGoogle Scholar
  36. 36.
    Von Hoff DD, Ervin TJ, Arena FP, et al (2012) Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol 30: (suppl 34; abstr LBA148)Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Mohamed A. Khalil
    • 1
  • Wei Qiao
    • 1
  • Peter Carlson
    • 2
  • Binsah George
    • 2
  • Milind Javle
    • 1
  • Michael Overman
    • 1
  • Gauri Varadhachary
    • 1
  • Robert A. Wolff
    • 1
  • James L. Abbruzzese
    • 1
  • David R. Fogelman
    • 1
    Email author
  1. 1.M.D. Anderson Cancer CenterHoustonUSA
  2. 2.University of Texas Health Science CenterHoustonUSA

Personalised recommendations